Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

Abstract

It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase (TrxR) activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated the reversal effects of Ethaselen on cisplatin resistance in K562/cisplatin (CDDP) cells that were established by pulse-inducing human erythrocyte leukemic cell line K562, which are fivefold more resistant to cisplatin compared to K562 cells. The morphology and growth showed that the adhesion of K562/CDDP further decreased while the cell volume increased. The proliferation of K562/CDDP is strengthened. The antitumor activities in vitro were assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and combination index (CI), showing the significant synergic effects of cisplatin and Ethaselen. Focusing on apoptosis, a series of comparisons was made between K562 and K562/CDDP. Cisplatin induced higher reactive oxygen species (ROS) generation in K562 and subsequently induced the formation of mitochondrial permeability transition pores (PTPs). In addition, cisplatin increased the ratio of Bax to Bcl-2 in K562, which can influence the mitochondrial membrane permeability. PTP formation and mitochondrial membrane permeabilization eventually resulted in the release of cytochrome c and activation of the Caspase pathway. However, these effects were not clearly seen in K562/CDDP, which may be the reason for the acquired CDDP resistance. However, Ethaselen can induce a high level of ROS in K562/CDDP by TrxR activity inhibition and increased ratio of Bax to Bcl-2 in K562/CDDP by nuclear factor κB (NF-κB) suppression, which subsequently induces the release of cytochrome c in K562/CDDP. This response is partly responsible for the reversal of the cisplatin resistance in K562/CDDP cells.

A thioredoxin reductase inhibitor ethaselen induces growth inhibition and apoptosis in gastric cancer

“…BBSKE, a novel organic selenium compound, is chosen as a candidate for anticancer agent because of its lower toxic effect [12,13,30,31,32] . In this work, BBSKE significantly induced TrxR inactivation in the four cancer cell lines paralleled with growth inhibition.…”

Phenylselanyl Group Incorporation for “Glutathione Peroxidase-Like” Activity Modulation

“…Similarly, to ebselen 1, a significant number of proven bioactive Se-molecules possess aromatic or heteroaromatic rings as the core of the molecule [3]. Examples are presented in Scheme 1 and also include other Se-therapeutics currently in clinical trial: ethaselen 2, Trx reductase inhibitor, antitumor agent [8] and 4,4-dimethyl-benziso-2H-selenazine 3, anti-inflammatory therapeutic tested in chronic plaque psoriasis [9]. with numerous examples of biologically active molecules [3][4][5][6], including the antioxidant agent Nphenylbenzisoselenazol-3(2H)-one (named as Ebselen) 1, currently in phase II clinical trial for noiseinduced hearing loss [7].…”

“…Similarly, to ebselen 1, a significant number of proven bioactive Semolecules possess aromatic or heteroaromatic rings as the core of the molecule [3]. Examples are presented in Scheme 1 and also include other Se-therapeutics currently in clinical trial: ethaselen 2, Trx reductase inhibitor, antitumor agent [8] and 4,4-dimethyl-benziso-2H-selenazine 3, antiinflammatory therapeutic tested in chronic plaque psoriasis [9]. Many research groups continue the study of new strategies and structural modifications to obtain new Se-antioxidants that have high and selective activity.…”

Extracellular Albumin Covalently Sequesters Selenocompounds and Determines Cytotoxicity

“…It is noteworthy that some types of cancer have been reported to be more susceptible to oxidative stress than normal cells [3,4]; SeCs hold the promise to outperform conventional chemotherapeutics in achieving targeted therapy [5]. In addition, upregulation of antioxidant defense system has been shown to underlie the development of chemoresistance [6]; thus, concomitant treatment of SeCs has been reported to re-sensitize resistant cancer cells [7]. In fact, two SeCs, selenite [8] and ethaselen [7], have been already used in clinical trials.…”

“…In addition, upregulation of antioxidant defense system has been shown to underlie the development of chemoresistance [6]; thus, concomitant treatment of SeCs has been reported to re-sensitize resistant cancer cells [7]. In fact, two SeCs, selenite [8] and ethaselen [7], have been already used in clinical trials. Inspired by the promising effects of SeCs and in order to further improve their treatment efficacy, several researchers have started to introduce Se into current treatments, including both small molecules (i.e.…”